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Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

Sandra M. Holley, Jack C. Reidling, Carlos Cepeda, Alice Lau, Cindy Moore, Iliana Orellana, Brian Fury, Lexi Kopan, Sylvia Yeung, Michael Neel, Dane Coleal-Bergum, Edwin S. Monuki, Charles K. Meshul, Gerhard Bauer, Michael S. Levine, Leslie M. Thompson
doi: https://doi.org/10.1101/2021.01.18.427078
Sandra M. Holley
1Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
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Jack C. Reidling
2Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine CA
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Carlos Cepeda
1Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
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Alice Lau
3Department of Psychiatry & Human Behavior, University of California Irvine, Irvine CA
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Cindy Moore
4Portland VA Medical Center, Portland, OR
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Iliana Orellana
2Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine CA
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Brian Fury
5Institute for Regenerative Cures University of California Davis, Sacramento, CA
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Lexi Kopan
2Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine CA
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Sylvia Yeung
2Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine CA
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Michael Neel
6Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA
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Dane Coleal-Bergum
5Institute for Regenerative Cures University of California Davis, Sacramento, CA
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Edwin S. Monuki
6Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA
7Sue and Bill Gross Stem Cell Center University of California Irvine, Irvine, CA
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Charles K. Meshul
4Portland VA Medical Center, Portland, OR
8Oregon Health & Science University, Department of Behavioral Neuroscience and Pathology, Portland, OR
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Gerhard Bauer
5Institute for Regenerative Cures University of California Davis, Sacramento, CA
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Michael S. Levine
1Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
9Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
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Leslie M. Thompson
2Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine CA
3Department of Psychiatry & Human Behavior, University of California Irvine, Irvine CA
7Sue and Bill Gross Stem Cell Center University of California Irvine, Irvine, CA
10Department of Neurobiology & Behavior University of California Irvine, Irvine CA
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  • For correspondence: lmthomps@uci.edu
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Abstract

Huntington’s disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

Footnotes

  • ↵† Co-first authors

  • ↵^ Co-senior authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 19, 2021.
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Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum
Sandra M. Holley, Jack C. Reidling, Carlos Cepeda, Alice Lau, Cindy Moore, Iliana Orellana, Brian Fury, Lexi Kopan, Sylvia Yeung, Michael Neel, Dane Coleal-Bergum, Edwin S. Monuki, Charles K. Meshul, Gerhard Bauer, Michael S. Levine, Leslie M. Thompson
bioRxiv 2021.01.18.427078; doi: https://doi.org/10.1101/2021.01.18.427078
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Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum
Sandra M. Holley, Jack C. Reidling, Carlos Cepeda, Alice Lau, Cindy Moore, Iliana Orellana, Brian Fury, Lexi Kopan, Sylvia Yeung, Michael Neel, Dane Coleal-Bergum, Edwin S. Monuki, Charles K. Meshul, Gerhard Bauer, Michael S. Levine, Leslie M. Thompson
bioRxiv 2021.01.18.427078; doi: https://doi.org/10.1101/2021.01.18.427078

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